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Group B streptococcus (GBS) is a common asymptomatic colonizer in acidic vagina of pregnant women and can transmit to newborns, causing neonatal pneumonia and meningitis. Biofilm formation is often associated with bacterial colonization and pathogenesis. Little is known about GBS biofilm and the effect of environmental stimuli on their growth along with biofilm formation. The objective of this study was to investigate the survival and biofilm formation of GBS, isolated from pregnant women, in nutrient-limited medium under various pH conditions. Growth and survival experiments were determined by optical density and viable counts. Crystal violet staining, scanning electron microscopy, and atomic force microscopy (AFM) were used to analyze the capacity of biofilm production. Our results showed that GBS isolates proliferated with increasing pH with highest maximum specific growth rate (μ) at pH 6.5, but survived at pH 4.5 for longer than 48 h. Biofilm formation of the 80 GBS isolates at pH 4.5 was significantly higher than at pH 7.0. This difference was confirmed by two other methods. The low elastic modulus obtained from samples at pH 4.5 by AFM revealed the softness of biofilm; in contrast, little or no biofilm was measured at pH 7.0. Under acidic pH, the capability of biofilm formation of serotypes III and V showed statistically significant difference from serotypes Ia and Ib. Our finding suggested that survival and enhanced biofilm formation at vaginal pH are potentially advantageous for GBS in colonizing vagina and increase the risk of vaginosis and neonatal infection. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and oral activity of two promising indoles, (2-(1 H-indol-3-yl)-1 H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound II] and (2-(1 H-indol-5-ylamino)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound IAT], in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo. Methods: The in vitro drug-like properties, including potency, solubility, metabolic stability, and drug-drug interactions were examined for our two active compounds. An in vivo pharmacokinetic study and antitumor efficacy study were also completed to compare their efficacy with docetaxel. Results: Both compounds bound to the colchicine-binding site on tubulin, and inhibited tubulin polymerization, resulting in highly potent cytotoxic activity in vitro. While the potency of paclitaxel and docetaxel was compromised in a multidrug-resistant cell line that overexpresses P-glycoprotein, the potency of compounds II and IAT was maintained. Both compounds had favorable drug-like properties, and acceptable oral bioavailability (21-50 %) in mice, rats, and dogs. Tumor growth inhibition of greater than 100 % was achieved when immunodeficient mice with rapidly growing paclitaxel-resistant prostate cancer cells were treated orally at doses of 3-30 mg/kg of II or IAT. Conclusions: These studies highlight the potent and broad anticancer activity of two orally bioavailable compounds, offering significant pharmacologic advantage over existing drugs of this class for multidrug resistant or taxane-refractory cancers. [ABSTRACT FROM AUTHOR]

Abstract: We previously reported the discovery of 2-aryl-4-benzoyl-imidazoles (ABI-I) as potent antiproliferative agents for melanoma. To further understand the structural requirements for the potency of ABI analogs, gain insight in the structure–activity relationships (SAR), and investigate metabolic stability for these compounds, we report extensive SAR studies on the ABI-I scaffold. Compared with the previous set of ABI-I analogs, the newly synthesized ABI-II analogs have lower potency in general, but some of the new analogs have comparable potency to the most active compounds in the previous set when tested in two melanoma and four prostate cancer cell lines. These SAR studies indicated that the antiproliferative activity was very sensitive to subtle changes in the ligand. Tested compounds 3ab and 8a are equally active against highly paclitaxel resistant cancer cell lines and their parental cell lines, indicating that drugs developed based on ABI-I analogs may have therapeutic advantages over paclitaxel in treating resistant tumors. Metabolic stability studies of compound 3ab revealed that N-methyl imidazole failed to extend stability as literature reported because de-methylation was found as the major metabolic pathway in rat and mouse liver microsomes. However, this sheds light on the possibility for many modifications on imidazole ring for further lead optimization since the modification on imidazole, such as compound 3ab, did not impact the potency. [Copyright &y& Elsevier]

In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-aryl-thiazole (SMART) template, we explored chemodiverse “B” rings and “B” to “C” ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-amino-thiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between “A” and “B” rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45a–c(PAT) vs 1(SMART)). [ABSTRACT FROM AUTHOR]

Abstract: DB-67 and its lactone homolog DB-91 are derivatives of topoisomerase I inhibitor camptothecin (CPT) with silyl moiety, which may exhibit a slower inactivation process by changed kinetics of protein binding and/or hydrolysis of its lactone ring and result in increased antitumor activity and decreased toxicity. Pharmacokinetic properties and antitumor activities of the two silatecans were studied and compared. The lactone ring of DB-91 is more stable than those of all the other CPT derivatives in mouse plasma. Both silatecans were metabolized faster than CPT in mouse and human liver microsomes. Pharmacokinetic study revealed a plasma elimination half-life (t 1/2) of 33 and 94min for DB-67 and DB-91, respectively; similar systemic exposure in plasma between DB-67 and DB-91; and similar volume of distribution at the steady state between DB-67 and DB-91, approximately 15-fold smaller than that of CPT. While DB-91 showed limited activities, DB-67 exhibited activities against the growth of in vivo-like histocultured human tumors and s.c. xenografted human tumors in nude mice. In conclusion, DB-67 is more effective, compared to DB-91, against human tumor growth in in vitro, in vivo-like and in vivo systems. Further pre-clinical and clinical investigations of DB-67 are warranted. [Copyright &y& Elsevier]

Abstract: The device and inverter characteristics based on InGaP/InGaAs n- and p-channel complementary pseudomorphic doped-channel HFETs are demonstrated. Particularly, the saturation voltage of the n-channel device is substantially reduced because the two-dimensional electron gas (2DEG) is formed and modulated in the InGaAs strain channel. Experimentally, an extrinsic transconductance of 109(11.5)mS/mm and a saturation current density of 32.5(−27)mA/mm are obtained for the n-channel (p-channel) device. Furthermore, the noise margins NMH and NML values are up to 1.317 and 0.28V, respectively, at a supply voltage of 2.0V for complementary logic inverter application. [Copyright &y& Elsevier]

Acrylamide, classified by the IARC as a probable human carcinogen (Group 2A), is present in cigarette mainstream smoke and also some high-temperature-processed foods, thus smokers and consumers of certain foods are at risk of acrylamide exposure. The objectives of this study were to analyze N-acetyl-S-(propionamide)-cysteine (NASPC), an acrylamide metabolite, in the urine of smokers and nonsmokers, and to investigate the association between acrylamide exposure and urinary NASPC levels in smokers and nonsmokers in order to validate NASPC as a biomarker for the assessment of acrylamide exposure. Urine samples from 63 male military officers were collected as well as background personal information and smoking habits using questionnaires. Acrylamide exposure from tobacco smoke was represented by self-reported daily cigarette consumption and urinary cotinine levels. NASPC and cotinine were analyzed using our newly developed liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) methods. Our results reveal a statistically significant linear relationship between urinary NASPC and cotinine levels for smokers (Spearman correlation coefficient r=0.402, P=0.028), but insignificantly so for nonsmokers. These results verify our suggestion that urinary NASPC could serve as a sensitive, specific, noninvasive, and easily accessible biomarker for low-dose acrylamide exposure as also exposure to carcinogens in tobacco smoke. Routine monitoring of urinary NASPC could be used to assess human exposures to acrylamide in the living environment and the workplace. [Copyright &y& Elsevier]

Blood leakage and resultant loss during haemodialysis therapy are life‐threatening complications. As the venous needles (at arterial/venous sites) disconnect from blood lines, little reaction time is left to stop the blood loss. The authors integrate the wireless flexible sensor with a virtual internal impedance model to design a warning tool to early detect blood leakage and further lower the mortality rate it causes. This flexible sensor is fabricated via a screen‐printing technique by printing electronic circuits on a soft substrate in an array configuration. The virtual internal impedance model employed is advantageous for both detecting if any short‐circuit branch resistance develops and estimating the virtual internal impedances of the sensor. Once the metering nodal voltage changes, the estimated quantity resistances and near infinite resistances are employed to separate a short circuit from an open circuit. The algorithm developed can be implemented in an embedded system via a wireless fidelity wireless network through cloud computing. The experimental results show feasibility and potential of specifications for commercial design. [ABSTRACT FROM AUTHOR]

A 45-y-old man was hospitalized due to pain and swelling of the right leg for 3 d. Bullae developed with gas formation involving multiple compartments of the entire limb 46 h later. Klebsiella pneumoniae was recovered from blood and surgical specimens. The patient died on Day 8 despite amputation and antibiotic therapy. [ABSTRACT FROM AUTHOR]

Atrial septal defect is a serious congenital heart disease. Interventional cardiac catheterization has increasingly become a treatment for its correction, with reduced risks for infections and complications of anesthesia. However, the cardiac catheterization still poses a huge challenge for novice surgeons; therefore a double-catheter system is warrant for training surgeons. In this study, a novel mechanical training system is designed for interventional cardiac catheterization simulation. Visual and haptic feedback simulators were developed from medical records to simulate accidental bumps into the vessel walls. The results indicate that this proposed system could accurately simulate the resistance encountered during cardiac catheterization and achieve the desired training outcomes. This simulation module can be a potential of teaching platform for training surgeons in medical education. [ABSTRACT FROM AUTHOR]

Target identification is one of the most critical steps following cell-based phenotypic chemical screens aimed at identifying compounds with potential uses in cell biology and for developing novel disease therapies. Current in silico target identification methods, including chemical similarity database searches, are limited to single or sequential ligand analysis that have limited capabilities for accurate deconvolution of a large number of compounds with diverse chemical structures. Here, we present CSNAP (Chemical Similarity Network Analysis Pulldown), a new computational target identification method that utilizes chemical similarity networks for large-scale chemotype (consensus chemical pattern) recognition and drug target profiling. Our benchmark study showed that CSNAP can achieve an overall higher accuracy (>80%) of target prediction with respect to representative chemotypes in large (>200) compound sets, in comparison to the SEA approach (60–70%). Additionally, CSNAP is capable of integrating with biological knowledge-based databases (Uniprot, GO) and high-throughput biology platforms (proteomic, genetic, etc) for system-wise drug target validation. To demonstrate the utility of the CSNAP approach, we combined CSNAP's target prediction with experimental ligand evaluation to identify the major mitotic targets of hit compounds from a cell-based chemical screen and we highlight novel compounds targeting microtubules, an important cancer therapeutic target. The CSNAP method is freely available and can be accessed from the CSNAP web server (). [ABSTRACT FROM AUTHOR]

Abstract: A series of (2RS,4R)-2-arylthiazolidine-4-carboxylic acid amide (ATCAA) was synthesized. Antiproliferative activity against melanoma and prostate cancer cells compared with control cells (fibroblast and RH7777, respectively) was evaluated. Compound 3id showed the best selectivity and growth-inhibition activity against three melanoma cell lines (B16-F1, A375, and WM-164). Compounds 15b and 3ac had good selectivity and potency against four prostate cancer cell lines (DU 145, PC-3, LNCaP, and PPC-1). The structure–activity relationship (SAR) of the side chain, the thiazolidine ring, and phenyl substituents is discussed. Cell cycle analysis showed that the percentage of cancer cells undergoing apoptosis (sub-G1 phase) increased after treatment with 1b and 3ad, which also strongly inhibited melanoma colony formation. In vivo studies on nude mice bearing A375 melanoma tumors showed that compound 1b inhibited tumor growth in a dose-dependent manner. At a dose of 10mg/kg, 1b significantly inhibited melanoma tumor growth and showed higher efficacy than did dacarbazine at 60mg/kg. [Copyright &y& Elsevier]

Abstract: The characteristics of InGaP/GaAs heterostructure-emitter bipolar transistors (HEBTs) including conventional GaAs bulk base, InGaAs/GaAs superlattice-base, and InGaAs quantum-well base structures are presented and compared by two-dimensional simulation analysis. Among of the devices, the superlattice-base device exhibits a highest collector current, a highest current gain and a lowest base–emitter turn-on voltage attributed to the increased charge storage of minority carriers in the InGaAs/GaAs superlattice-base region by tunneling behavior. The relatively low turn-on voltage can reduce the operating voltage and collector–emitter offset voltage for low power consumption in circuit applications. However, as to the quantum-well base device, the electrons injecting into the InGaAs well are blocked by the p+-GaAs bulk base and it causes a great quantity of electron storage within the small energy-gap n-type GaAs emitter layer, which significantly increases the base recombination current as well as degrades the collector current and current gain. [Copyright &y& Elsevier]

Although exertional dyspnea and worsening hypoxia are hallmark clinical features of idiopathic pulmonary fibrosis ( IPF), no drug currently available could treat them. GBT1118 is a novel orally bioavailable small molecule that binds to hemoglobin and produces a concentration-dependent left shift of the oxygen-hemoglobin dissociation curve with subsequent increase in hemoglobin-oxygen affinity and arterial oxygen loading. To assess whether pharmacological modification of hemoglobin-oxygen affinity could ameliorate hypoxemia associated with lung fibrosis, we evaluated GBT1118 in a bleomycin-induced mouse model of hypoxemia and fibrosis. After pulmonary fibrosis and hypoxemia were induced, GBT1118 was administered for eight consecutive days. Hypoxemia was determined by monitoring arterial oxygen saturation, while the severity of pulmonary fibrosis was assessed by histopathological evaluation and determination of collagen and leukocyte levels in bronchoalveolar lavage fluid. We found that hemoglobin modification by GBT1118 had strong antihypoxemic therapeutic effects with improved arterial oxygen saturation to near normal level. Moreover, GBT1118 treatment significantly attenuated bleomycin-induced lung fibrosis, collagen accumulation, body weight loss, and leukocyte infiltration. This study is the first to suggest the beneficial effects of hemoglobin modification in fibrotic lungs and offers a promising and novel therapeutic strategy for the treatment of hypoxemia associated with chronic fibrotic lung disorders in human, including IPF. [ABSTRACT FROM AUTHOR]

Acrylamide (AA), a rodent carcinogen,is widely used in industryand present in cigarette smoke as well as in foods processed at hightemperatures. The metabolic activation of AA to glycidamide (GA) couldbe critical for AA carcinogenicity since GA causes DNA adduct formation in vivo. N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GAG), the most abundant DNA adduct of AA, is subjectedto spontaneous and enzymatic depurination and excreted through urine.Urinary N7-GAG analysis can confirm AA genotoxicity and identify activespecies of AA metabolites in humans, thereby serving as a risk-associatedbiomarker for molecular epidemiology studies. This study aimed todevelop an isotope-dilution solid-phase extraction liquid chromatographytandem mass spectrometry method to comparatively analyze urinary N7-GAGlevels in nonsmokers and smokers. Urinary N-acetyl-S-(propionamide)-cysteine (AAMA), a metabolite of AA, wasalso analyzed as a biomarker for current AA exposure. Urinary N7-GAGwas quantified by monitoring m/z239 → 152 for N7-GAG and m/z242 → 152 for 13C3-labeled N7-GAG underpositive electron spray ionization and multiple reaction mode. Themedian urinary N7-GAG level was 0.93 μg/g creatinine in nonsmokers(n= 33) and 1.41 μg/g creatinine in smokers(n= 30). Multiple linear regression analysis ofdata revealed that N7-GAG levels were only significantly associatedwith AAMA levels. These results demonstrate that urinary N7-GAG ofnonsmokers and smokers is significantly associated with a very lowlevel of dietary AA intake, assessed by analyzing urinary AAMA. [ABSTRACT FROM AUTHOR]

Toblock the metabolically labile sites of novel tubulin inhibitorstargeting the colchicine binding site based on SMART, ABI, and PATtemplates, we have designed, synthesized, and biologically testedthree focused sets of new derivatives with modifications at the carbonyllinker, the para-position in the C ring of SMART template, and modificationof A ring of the PAT template. Structure–activity relationshipsof these compounds led to the identification of new benzimidazoleand imidazo[4,5-c]pyridine-fused ring templates,represented by compounds 4and 7, respectively,which showed enhanced antitumor activity and substantially improvedthe metabolic stability in liver microsomes compared to SMART. MOMgroup replaced TMP C ring and generated a potent analogue 15, which showed comparable potency to the parent SMART compound. Furthermodification of PAT template yielded another potent analogue 33with 5-indolyl substituent at A ring. [ABSTRACT FROM AUTHOR]

Abstract: Vancomycin-resistant (VR) enterococci (VRE) are increasingly important nosocomial pathogens, commonly causing catheter-related urinary tract infections or vascular catheter-related bloodstream infections. In this study, 10 Enterococcus faecium and 9 Enterococcus faecalis different pulsed-field gel electrophoresis genome-type VR clinical isolates were detected. The potential role of fosfomycin-based combination regimens for biofilm-related VRE infection is in vitro evaluated. Anti-VRE activities of fosfomycin, ampicillin, linezolid, minocycline, rifampicin, tigecycline, teicoplanin, vancomycin alone, or fosfomycin-based combinations were studied by time-kill method and a biofilm model. Of the fosfomycin-based combinations, a synergistic effect was particularly noted for teicoplanin against 89% of the VR E. faecalis isolates. In a biofilm model, only linezolid alone was able to reduce the bacterial loads, and the use of fosfomycin-based combinations, excluding rifampicin (40%), failed to enhance antibacterial activity against VR E. faecium. For E. faecalis, an inhibitory effect was evident using ampicillin alone or fosfomycin plus rifampicin (100%), tigecycline (56%), or teicoplanin (44%). However, an antagonistic effect was found for ampicillin plus fosfomycin against 2 of 3 of the VR E. faecalis isolates. The antibacterial activities of the drugs tested against VRE in vitro varied by species. Ampicillin exhibited potential activity against planktonic- and biofilm-embedded VR E. faecalis. Fosfomycin-based combinations may have enhanced antibacterial effects against VRE even in the biofilm model, and this observation warrants further clinical studies. [Copyright &y& Elsevier]

Purpose: To evaluate abilities of 2- aryl-4- benzoyl- imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy. Methods: MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human melanoma xenograft were used to evaluate ABI in vivo antitumor activity. B16-F10/C57BL mouse melanoma lung metastasis model was used to test ABI efficacy to inhibit tumor lung metastasis. Results: ABIs showed similar potency to MDR cells compared to matching parent cells. ABIs were identified to target tubulin on the colchicine binding site. After 31 days of treatment, ABI-288 dosed at 25 mg/kg inhibited melanoma tumor growth by 69%; dacarbazine at 60 mg/kg inhibited growth by 52%. ABI-274 dosed at 25 mg/kg showed better lung metastasis inhibition than dacarbazine at 60 mg/kg. Conclusions: This new class of antimitotic compounds can overcome several clinically important drug resistant mechanisms in vitro and are effective in inhibiting melanoma lung metastasis in vivo, supporting their further development. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, the device performance and complementary inverter of the InGaP/InGaAs/GaAs doped-channel field-effect transistors (DCFETs) by two-dimensional semiconductor simulation are demonstrated. Due to the relatively large conduction (valance) band discontinuity at InGaP/InGaAs interface, it provides good confinement effect for transporting carriers in InGaAs channel layer for the n-channel (p-channel) device. The large gate turn-on voltage is achieved due to the employment of the wide energy-gap InGaP material as gate layer. The and are of 6.5 (2.1) and 25 (5) GHz for the n-channel (p-channel) device. Furthermore, the co-integrated structures, by the combination of n- and p-channel field-effect transistors, could form a complementary inverter and the relatively large noise margins are achieved. [Copyright &y& Elsevier]

Abstract: A novel InGaP/GaAs heterostructure-emitter bipolar transistor (HEBT) with InGaAs/GaAs superlattice-base structure is proposed and demonstrated by two-dimensional analysis. As compared with the traditional HEBT, the studied superlattice-base device exhibits a higher collector current, a higher current gain of 246, and a lower base–emitter (B–E) turn-on voltage of 0.966V at a current level of 1μA, attributed to the increased charge storage of minority carriers in the InGaAs/GaAs superlattice-base region by tunneling behavior. The low turn-on voltage can reduce the operating voltage and collector–emitter offset voltage for low power consumption in circuit applications. [Copyright &y& Elsevier]

Studies of the pathogenesis of dengue hemorrhagic fever (DHF), a potentially life-threatening disease, have revealed the importance of initial high levels of virus replication. However, the possible involvement of virus during the transition from fever to defervescence, a critical stage in determining the severity of disease, has not been appreciated. Using quantitative reverse transcription-polymerase chain reaction, we examined the levels of plasma dengue viral load during both fever and defervescence periods in patients from a DEN-3 outbreak in southern Taiwan in 1998. Higher levels of plasma dengue viral RNA were found in DHF patients than in DF patients. During defervescence, while the level of plasma dengue viral RNA was undetectable in most DF patients, it remains high in all DHF patients. Using a modified immunoprecipitation assay, we demonstrated for the first time that the plasma dengue viruses persisting during defervescence were in the immune complexes for most DHF patients. These findings suggest that continued active viral replication or delay in the clearance of viremia contributes to the pathogenesis of DHF. Moreover, high levels of plasma dengue viral RNA during defervescence may serve as a disease marker for DHF. [Copyright &y& Elsevier]